This invention relates to novel compounds which are substituted dodecahydrotriphenylenes, decahydro-1H-cyclopenta[1]phenanthrenes, decahydro-1H-pyrido[1,2-f]phenanthridines and decahydropyrrolo[1,2-f]phenanthridines and which are useful in mammals, including man, as CNS agents, especially as analgesics, tranquilizers, and antiemetics, as antidiarreals, as antitussives, as diuretics and as agents for the treatment of glaucoma; and as intermediates therefor.
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesic agents such as d-propoxyphene, codeine, and morphine, possess addictive liability. The need for improved and potent analgesic agents is, therefore, evident.
There is also a continuing need for potent antiemetic agents having minimal side-effects, particularly in patients receiving cancer chemotherapy.
The analgesic properties of 9-nor-9beta-hydroxyhexahydrocannabinol and related compounds have been reported by Wilson and May, J. Med. Chem. 17, 475-476 (1974); 18, 700-703 (1975). The antiemetic activity of delta.sup.9 -tetrahydrocannabinol in patients undergoing cancer chemotherapy has been reported by Sallan et al. New England J. Med. 293, 795 (1975).
Various 5,6,6a,7,8,9,10,10a-octahydro-9-(oxo or hydroxy)-1-hydroxy-3-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl, or aryloxyalkyl)phenanthridine derivatives have been reported to possess various medicinal properties particularly, analgesic activity, Johnson, U.S. Pat. No. 4,260,764, as well as antiemetic activity, Johnson and Milne, U.S. Pat. No. 4,228,169, Nov. 14, 1980.
Various 1,2,3,4,4a,9,10,10a-octahydro-3-(oxo or hydroxy)-5-hydroxy-7-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl, or aryloxy)phenanthrenes are also reported to possess analgesic activity, Althuis et al., U.S. Pat. No. 4,188,495 (Feb. 12, 1980).
Various 6a,7,8,9,10,10a-hexahydro-9-amino-1-hydroxy-3-alkyl-6H-benzo[c]chromene derivatives are reported to be useful as analgesics, antidepressants, antianxiety, and hypotensive agents, Day et al., U.S. Pat. No. 4,152,450 (May 1, 1979); while various 7,8,10,10a-tetrahydro-1-hydroxy-3-alkyl-6H,6aH-benzo[c]chromen-9-one derivatives are reported as antiemetic drugs, Archer et al., U.S. Pat. No. 4,087,545 (May 2, 1978), and earlier as having antidepressant, analgesic and antianxiety properties, Archer, U.S. Pat. Nos. 3,953,603 (Apr. 27, 1976), 3,944,673 (Mar. 16, 1976) and 3,928,598 (Dec. 23, 1975).
Johnson, U.S. Pat. No. 4,309,545 (Jan. 5, 1982) discloses 5,6,6a,7,8,9,10,10a-octahydro-9-amino-1-hydroxy-3-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl or aryloxyalkyl)phenanthridine derivatives as having CNS activity, particularly useful as analgesics and antiemetics.
U.S. Pat. No. 4,476,131 and its divisional U.S. Pat. No. 4,576,964 disclose various 1,2,3,4,4a,9,10,10a-octahydro-9-(substituted)-8-hydroxy-6-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl or aryloxyalkyl)phenanthrene, 2,3,3a,4,5,9b-hexahydro-5-(substituted)-6-hydroxy-8-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl or aryloxyalkyl)cyclopenta[a]naphthalene, 2,3,4,4a,5,6-hexahydro-6-(substituted)-7-hydroxy-9-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl or aryloxyalkyl)-1H-pyrido[1,2-a]quinoline and 1,2,3,3a,4,5-hexahydro-5-(substituted)-6-hydroxy-8-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aralkoxyalkyl or aryloxyalkyl)pyrrolo[1,2-a]quinoline derivatives having similar CNS activity.
The nomenclature employed herein is based on Rigaudy and Klesney, I.U.P.A.C. Nomenclature of Organic Chemistry--1979 Edition, Permangon Press, New York, including the use of R and S to designate absolute stereochemistry and R* and S* to designate relative stereochemistry. Formulae showing dotted and heavy bonds are generally intended to specify relative stereochemistry, unless otherwise specified in the text.